Autism subtypes identified using cross-species functional connectivity analyses

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Phenotypic heterogeneity in autism is assumed to stem from biological differences, but direct evidence is scarce.
• Understanding these underlying biological variations is crucial for developing targeted interventions.

Purpose of the Study:

• To investigate whether brain connectivity patterns in autism can be biologically classified into distinct subtypes.
• To explore the biological pathways associated with these subtypes across species.

Main Methods:

• Cross-species functional neuroimaging using functional magnetic resonance imaging (fMRI).
• Analysis of connectivity patterns in 20 genetic mouse models of autism and a large human dataset (940 autistic, 1036 neurotypical individuals).
• Clustering of fMRI data to identify hypoconnectivity and hyperconnectivity subtypes.

Main Results:

• Autism-related fMRI connectivity alterations cluster into hypoconnectivity-dominant and hyperconnectivity-dominant subtypes in both mice and humans.
• Hypoconnectivity subtypes are linked to synaptic dysfunction, while hyperconnectivity subtypes are associated with transcriptional and immune alterations.
• Human subtypes are replicable, show distinct network architectures and behaviors, and mirror the biological pathways found in mice.

Conclusions:

• Brain connectivity patterns in autism exhibit biologically distinct subtypes, challenging the notion of a single autism pathobiology.
• Identified subtypes provide an empirical framework for more precise subtyping of autism spectrum disorder.
• Findings highlight the importance of considering synaptic and immune-related pathways in autism research.